Quick Links

How would you like to share?

The energy needs of neurons are prodigious—the brain makes up just a small percentage of the body, yet burns roughly 25 percent of its calories (Leonard et al., 2007). That hunger for energy requires that mitochondria stay in tip-top shape, and indeed, a drop-off in their function is associated with Alzheimer disease, Parkinson disease, and other neurodegenerative conditions (for a review, see Reddy and Beal, 2008). Now, a study from Roberta Diaz Brinton and colleagues at the University of Southern California, Los Angeles, shows that flagging energy generation starts very early and gets worse with age in a mouse model of AD. In a paper published August 10 in PNAS online, Brinton and coworkers report mitochondrial deficits in embryonic neurons from female mice expressing a trio of AD-related proteins. The observed malfunction of mitochondria worsens when the animals reach reproductive senescence (the mouse equivalent of human menopause). The results indicate that mitochondrial problems begin long before amyloid deposition begins, and thus may be a causal contributor to the development of AD pathology in these mice. In addition, the coincident timing of estrogen loss and worsening mitochondrial dysfunction suggests that the neuroprotective actions of estrogen may stem from its ability to preserve brain energetics.

Women account for 68 percent of cases of AD, and one commonly offered explanation for their overrepresentation is that they simply live longer than men do and so have a greater age-related risk of developing dementia. However, Brinton told ARF she thinks there is more to it. Her previous work showed that estrogen keeps mitochondria ticking along, and loss of estrogen causes a 20-30 percent drop in glucose metabolism and mitochondrial function (Irwin et al., 2008). AD is also associated with lower levels of some mitochondrial enzymes, lower glucose uptake, and higher oxidative stress, so Brinton wondered what it means to lose 30 percent of one’s bioenergy portfolio. Could a drop in mitochondrial function at menopause be contributing to AD?

Mitochondrial function also decreased with age in normal mice, but the decline overall was steeper in the AD mice. The differences between normal and transgenic animals were greatest after nine months, when the mice enter reproductive senescence. This also corresponded to the time when Aβ appeared in the mitochondria, as measured by Western blot for a 16 kDa Aβ oligomer, or as the Aβ-alcohol dehydrogenase complex previously implicated in mitochondrial dysfunction (see ARF related news story on Lustbader et al., 2004). This is consistent with much previous work showing that loss of estrogen cranks up amyloid production, including specifically in the 3xTg mice (Carroll et al., 2007).

The results at three months indicated that mitochondria were malfunctioning before significant amyloid pathology appeared. The researchers wanted to know when the trouble started, so they looked at cultured embryonic hippocampal neurons. Even at that early time, they found decreased oxygen consumption and increased glycolysis. When they measured mitochondrial capacity by treating the cells with a mitochondrial uncoupler, the researchers found that cells from the transgenic mice revealed a lower overall respiratory capacity than did normal mice. “The AD mouse simply cannot rise to the metabolic challenge,” Brinton says. This may bode poorly for the neurons as their energy demands increase, though just why the mitochondria are affected is unclear. “It has to be one of the three transgenes, and that is something we are testing right now,” she said.

“The most important finding is that a metabolic mitochondrial deficit precedes the development of AD pathology, by a substantial amount of time, suggesting that there is a slow inexorable deficit in the bioenergetics in the brain that leads to development of AD pathology,” Brinton says. The results are consistent with epidemiological observation that children whose mothers had AD are at a higher risk for the disease whether they are male or female. Since mitochondrial genes are inherited through the maternal line, that suggests that some of those genes may predispose to AD, possibly by affecting energy metabolism (Mosconi et al., 2009).

The results also provide a potential explanation for the neuroprotective effects of estrogen, and a rationale for using the hormone to protect mitochondria. Early epidemiological studies indicated that women on hormone replacement therapy had lower risk for developing AD. Later, the Women’s Health Study showed the opposite (see ARF live discussion), but those women started estrogen at age 65, not at menopause as in the earlier studies. Since then, additional work has shown that women who have their ovaries removed pre-menopausally have an increased risk of AD and Parkinson disease (see ARF related news story on Rocca et al, 2007). Is this due to effects of estrogen on mitochondria? That is not clear, but Brinton says that they are currently testing the idea that estrogen depletion acts via mitochondria to promote AD pathology in mouse models.

“The data suggest that the time to intervene to increase estrogen is not at the time of AD diagnosis, but at the time of loss of estrogen," says Brinton. “We need to take seriously this window of opportunity for a prevention strategy.” One idea Brinton’s lab and others are working on is brain-selective estrogen receptor modulators that target the estrogen receptor B, which is present in brain but low in other estrogen target tissues including breast and uterus (Tiwari-Woodruff et al., 2007; Zhao et al, 2007). Closer to the clinic is an estrogen receptor β-selective plant-based phytoestrogen preparation that Brinton is planning to test for the prevention of hot flashes in menopausal women. If that works, it may provide an alternative strategy to fine-tune estrogen replacement for the benefit of the brain.—Pat McCaffrey